Cancer is a devastating disease afflicting all communities worldwide. It has been estimated that 1 out of 2 men and 1 out 3 women will develop some form cancer within their lifetime.
Interestingly, it has been recently established that, regardless of the phenotypic variability between different cancer types, perturbation of limited number of genetic elements is sufficient to induce cellular transformation in many different human cell types (reviewed in Zhao et al., Trends Mol Med, 2004, 10: 344-350). Experimentally, it was demonstrated that activation of Ras and telomerase (TERT), along with inactivation of the tumor suppressor proteins p53 and Retinoblastoma protein (Rb) can immortalize a variety of human cell types, which can subsequently transform to a tumorigenic state in response to inhibition of protein phosphatase 2A (PP2A) (Mumby, Cell, 2007, 130(1):21-24; Westermarck and Hahn, Trends Mol. Med., 2008, 14(4):152-160; Zhao et al., Trends Mol Med, 2004, 10: 344-350). Therefore, these common genetic elements could be considered as master regulators of cancer development (Zhao et al., Trends Mol Med, 2004, 10: 344-350).
PP2A is a widely conserved protein serine/threonine phosphatase (PSP) that functions as a trimeric protein complex consisting of a catalytic subunit (PP2Ac or C), a scaffold subunit (PR65 or A), and one of the alternative regulatory B subunits. As described above, recent experimental evidence has firmly established that inhibition of PP2A activity is a prerequisite for human cell transformation (reviewed in Westermarck and Hahn, Trends Mol. Med., 2008, 14(4):152-160). Nevertheless, very little is known about mechanisms regulating PP2A complex composition and/or activity in vivo. Identification of PP2A inhibiting mechanisms might provide opportunities for development of novel class of cancer therapeutics re-activating PP2A tumor suppressor activity. This idea would be similar to cancer therapy approaches aiming at re-activation of tumor suppressor activity of p53 by small-molecules such as Nutlin-3 (Vassilev et al., Science, 2004, 303:844-48).
Protein phosphatase methylesterase 1 (PME-1) has been identified as a cancer-associated PP2A-interacting protein (Puustinen et al., Cancer Res., 2009, 69:2870-2877). Earlier biochemical studies had established PME-1 as a protein that inhibits PP2A activity via its enzymatic methylesterase activity required for demethylation of the conserved leucine 309 on catalytic PP2Ac subunit (Janssens et al., Trends Biochem. Sci., 2008, 33:113-21). An alternative mechanism by which PME-1 inhibits PP2A activity was proposed by structural analysis of PME-1-PP2A complex demonstrating that PME-1 directly binds to catalytic cleft of the PP2Ac subunit (Xing et al., Cell, 2008, 133:154-163). However, the functional relevance of PME-1 or its role in regulation of cellular signaling had not been addressed. PME-1 expression has been reported to correlate with human glioblastoma (GBM) progression, and with proliferation, as well as ERK MAPK pathway activity in human patient samples of GBM. Experimentally it was shown that PME-1 inhibition by siRNA inhibited ERK pathway activity and malignant cell growth (Puustinen et al., Cancer Res., 2009, 69:2870-2877). However, loss of PME-1 did not induce efficient cell death regardless of its potent effects on inhibition of malignant cell growth (Puustinen et al., Cancer Res., 2009, 69:2870-2877).
Cell killing and/or apoptosis are the preferable endpoints for cancer therapy regimens. On the other hand, either intrinsic or acquired resistance is the major problem related to currently used chemotherapies. Thus, although at least some of the mechanisms underlying malignancy have been revealed, there exists a need in the art for the development of medicaments for hyperproliferative diseases and especially cancer.